Defective DNA damage repair pathways and gene mutations in transcriptional pathways have been established as predominant targets for poly (ADP-ribose) polymerase (PARP) inhibition therapy in a wide spectrum of cancers (1-4). PARP-1, a nuclear enzyme, plays a crucial role in the DNA repair pathways in a cell, rendering it the ‘Achilles Heel’ in cancer therapy. PARP inhibitor therapy is particularly effective through a synthetic lethality mechanism in tumors where genetic mutations, such as BRCA for breast and ovarian cancer and PTEN for prostate cancers, lead to defects in the DNA repair pathways (4,15). Olaparib is an orally active PARP inhibitor, which competitively binds to the NAD+ binding site of PARP, thus attenuating the single strand DNA repairing mechanisms intervened by PARP (5-7). Olaparib and other PARP inhibitors are well established radiosensitizers as they effectively sensitize various cancers to radiation therapy by inhibiting the PARP activation due to DNA damage thus enhancing the tumor destruction in several cancers (8,9), especially in prostate cancers (10-13).
Presentation of castration-resistant prostate cancer (CRPC) is a major cause for fatalities in prostate cancer patient cohorts, either as localized or metastasized cancer (mCRPC) (20-22). Several studies have postulated and derived the synthetic lethality associated with PARP-1 inhibition and PTEN deficiency in prostate cancers (23), which is similar to BRCA mutations in breast and ovarian cancers (7,24). PARP-1 inhibition also has therapeutic implications specifically in the CRPC models of prostate cancer, where it appears to have cross talks with ligand independent aberrant androgen receptor (AR) activity, rendering the cancer insensitive to androgen depletion therapy (25). In addition, PARP-1 is also involved in the AR sensitive cancers where it is enzymatically linked to AR activity and progression of cancer (25). Specific gene fusions (TMPRSS2:ERG fusions) (26) and chromosomal rearrangements including PTEN and TP53 mutations are frequently detected in prostate cancers that are prone to become castration resistant (27-29).
Olaparib is currently being tested via oral administration in several clinical trials for a variety of cancers including prostate, pancreatic (14), breast (4,15) and ovarian cancers (4). The current treatment regimen followed in clinical trials with Olaparib includes p.o. administration at 400 mg b.i.d (3,4). Although promising, the pharmacokinetic profile derived from several clinical trials suggests that the oral treatment regimen with olaparib faces the following limitations: 1) The patient is required to follow a cumbersome routine of swallowing 16 capsules every day. 2) No dose dependent accumulation has been observed at the tumor site (15). 3) Olaparib is rapidly eliminated from the circulation in about 6 to 7 hrs and has poor bioavailability due to first pass metabolism into non-therapeutic metabolites. These limitations indicate that there is a compelling need for alternative delivery methods for olaparib and other PARP inhibitors.